Project Summary/Abstract Non-melanoma skin cancer (NMSC) is the most common form of cancer, and although ease of detection and surgical management results in good outcomes for a majority of patients, approximately 9,000 people succumb to metastatic disease in the US each year. Basal Cell Carcinoma (BCC) is the most common and generally benign form of skin cancer, but can result in significant morbidity. Squamous Cell Carcinoma (SCC) is less common, but has a much higher propensity for metastatic spread and is thus responsible for the majority of NMSC deaths. While both these neoplasms are thought to arise from keratinocytes in the skin, it is unclear what determines histological subtype (?tumor cell identity?) or what drives the dramatically different incidence and clinical characteristics. This R21 project will address the NCI's Provocative Question #4: Why do some closely related tissues exhibit dramatically different cancer incidence? We hypothesize that the underlying transcriptional state of a cell determines the probability of transformation and dictates tumor cell identity in response to oncogenic insults. In order to test this hypothesis, we will develop novel murine models of cutaneous BCC and SCC using tissue-specific, inducible Cre Recombinase to create mice harboring oncogenic lesions in skin keratinocytes. Importantly, we will use genetic alterations that are common to both BCC and SCC, which will allow us to evaluate differential responses of keratinocyte sub-populations to similar oncogenic stresses. Whole genome analysis of transcriptional changes in response to oncogenic insult will be combined with an examination of the underlying chromatin structure in keratinocytes in order to evaluate the impact of the basal transcriptional landscape on tumor incidence and tumor cell identity. We will translate our murine findings to human biology using our extensive collection of cultured primary human keratinocytes and SCC cell lines, as well as primary human tumors obtained from the High-Risk Skin Cancer Clinic at the Dana- Farber / Brigham and Women's Cancer Center. Understanding how cells make fate decisions following oncogenic insult will give insight into the mechanisms governing the differential incidence of tumors with unique histology arising in the same tissue and in tissues with similar developmental lineages.